Pathophysiologically based management of pulmonary hypertension of the newborn

Acute pulmonary hypertension of arterial (classic) origin

Due to the complexity of interactions between PVR, lung aeration, and myocardial adaptation, perinatal transition is a time of heightened vulnerability for the newborn cardiovascular system. Perturbations in this physiological framework due to any combination of perinatal hypoxia-ischemia, infection, and/or pulmonary parenchymal disease may interfere with the normal physiological decline in PVR and result in development of aPH. As a result of the elevated PVR in arterial (classic) aPH, hypoxic vasoconstriction ensues, which is an adaptive response to optimize ventilation-perfusion (V/Q) matching. Poor lung recruitment and overdistension from positive pressure ventilation can worsen hypoxic vasoconstriction, due to both increases in PVR and impaired carbon dioxide clearance, resulting in acidosis. It is important to realize that PVR is lowest at optimal lung recruitment, that is, at or near FRC. With excessive lung volume, some pulmonary capillaries undergo narrowing and stretching, whereas reduced lung volume can lead to capillary tortuosity or kinking, both of which increase PVR. Careful titration of positive pressure ventilation based on clinical, blood gas, and radiological assessment is therefore necessary. Particular care should be taken to avoid lung overinflation in the setting of hypoxic-ischemic encephalopathy, where lung compliance and FRC may be normal and hypoxemia instead a manifestation of altered pulmonary vascular reactivity. Overly aggressive attempts at lung recruitment in this context may be complicated by further impairments in PBF, as well as systemic compromise from reductions in LV stroke volume and LV end-diastolic volume (LVEDV). Over-distension also has the potential to compromise pulmonary venous flow, which may be difficult to distinguish clinically from progression of aPH driven by high PVR. Additional non-pulmonary factors related to either the underlying disease process, such as sepsis, perinatal asphyxia, and hypovolemia, or iatrogenesis, such as treatment with vasopressors that can cause pulmonary vasoconstriction (e.g., high-dose dopamine), may further drive increases in PVR. Elevated PVR leads to increased RV afterload and bidirectional or right-to-left shunting through the PFO and PDA. Right-to-left atrial shunting contributes to a reduction in RV preload. Right-to-left ductal shunting, though contributing to hypoxemia and reduced PBF, may provide a pop-off mechanism for the RV exposed to high afterload and an additional source of post-ductal perfusion where there is significant LV impairment.

Elevated pulmonary pressure results in a reduction in the pressure gradient between the RV cavity and the pulmonary vascular bed. The initial increase in RV afterload results in compensatory RV hypertrophy and increased contractility (referred to as “coupling” or homeometric adaptation). Increased contractility is mediated by changes in the sarcomere length-tension relationship and cardiomyocyte force-frequency relationship and increased calcium sensitivity. The force-frequency relationship describes the adaptive response of the neonatal myocardium to tachycardia, leading to improved force generation with increasing heart rate. To maintain cardiac output in the face of increased afterload, the RV dilates and heart rate increases. These changes preserve stroke volume initially by way of the increase in stroke volume associated with increased preload – via the Frank-Starling mechanism, with a larger ventricle emptying proportionally less blood – and an intact force-frequency response. This process is referred to as heterotopic adaptation. Unable to generate sufficient pressure for complete ejection of blood with each cardiac beat, RV emptying becomes progressively inadequate, leading to an increase in RV end-systolic pressure and, because less blood is ejected during systole, an increase in RV end-diastolic pressure. In addition, the force-frequency response is blunted as cardiac dysfunction develops. Progressive dilatation increases wall stress and myocardial oxygen consumption and eventually leads to a reduction in stroke volume. RV dilatation also changes the configuration of the cardiac chamber into one that is more spherical, which is associated with functional regurgitation across the tricuspid valve and increased right atrial pressure. Where elevation of PVR is excessive and sustained, ischemia, hypoxemia, and myocardial stretching lead to progressive RV dysfunction and uncoupling. ^, This is associated with leftward bowing of the interventricular septum (IVS), which is caused by prolonged contraction of the RV free wall when compared with the septum or LV free wall, impairing diastolic LV filling. Together with RV dilation, this leads to further impairment of RV function and decreased PBF. Through ventricular interdependence, the leftward shift in septal configuration also reduces LVEDV, LV stroke volume, and RV systolic contractile force, ^, resulting in systemic hypoperfusion, acidosis, and further reductions in PBF. In some infants a cycle of reduced PBF, worsening acidosis, hypoxemia, ventilation-perfusion mismatch, and cardiac dysfunction may develop, with a clinical phenotype of hypoxemic respiratory failure and cardiocirculatory impairment.

Acute pulmonary hypertension related to excessive pulmonary blood flow

Increased pulmonary blood flow, such as that observed in left-to-right shunt lesions, may result in elevations in pulmonary arterial pressure. The most obvious mechanism for this is an increase in pressure driven by increased flow through a circuit with a finite capacity to expand to accommodate the additional circulating volume. Muscular hypertrophy of the pulmonary vasculature, with secondary elevation in PVR, also occurs in response to a sustained increase in PBF. ^, An additional contributor is a disturbance of endothelial function resulting in altered pulmonary vasoreactivity; specifically, selective impairment of endothelium-dependent pulmonary vasodilation. Based on animal models, this may be attributable to both high basal activity of nitric oxide (NO) that is not readily increased and dysregulation of endothelial NO synthase, induced by increased pulmonary blood flow and pulmonary hypertension. This attenuates the fetal endothelial release of NO in response to sheer stress such as that generated by excessive pulmonary blood flow and may contribute to elevated mPAP in this setting.

Newborns with large preductal systemic to venous connections resulting in high-volume shunts are particularly at risk of complications from right heart pressure and volume loading. For example, the vein of Galen aneurysmal malformation (VGAM) is a rare cerebral arteriovenous malformation (AVM) with major hemodynamic implications. In utero, the low resistance of a cerebral AVM is balanced by the low-resistance placental circuit. With removal of the placenta and transition to the high afterload systemic neonatal circulation, up to 70% of the cardiac output is directed toward the cerebral vasculature. Superior vena caval flow may be up to 10 times normal, reflecting high flow through the AVM. This may result in a profound reduction in lower body perfusion, with lactic acidosis and post-ductal arterial hypotension. The ventricles receive increased preload, which in the case of the RV must be ejected against increased afterload, predisposing to RV dysfunction and failure. Supra-systemic pulmonary hypertension occurs, which is associated with right to left shunting at atrial and ductal levels. ^, This perpetuates hypoxemia, which further compromises ventricular performance. Chronic volume and pressure loading leads to RV dilation, which increases susceptibility to afterload-mediated dysfunction as adaptive mechanisms fail. RV coronary perfusion normally occurs throughout systole and diastole and is characterized by a lower flow and oxygen extraction when compared with the LV. The maladaptive, dilated, and hypertrophied RV has a higher oxygen requirement and inefficient oxygen utilization, with coronary perfusion limited to diastole by the increased RV pressure. Elevations in RV end-diastolic pressure, leading to increased right atrial and central venous pressure, and therefore reduced diastolic coronary flow to the RV constitute a potential additional source of impaired perfusion in the setting of PH. Intracranial vascular “steal” through the AVM, which is associated with retrograde diastolic descending aortic flow, may further compromise tenuous coronary perfusion via low coronary root pressure, creating a “pseudocoarctation” physiology. This effect is additive with the increased ventricular pressure in reducing subendocardial perfusion, contributing to myocardial ischemia and RV dysfunction. Non-judicious use of pulmonary vasodilators may exacerbate these effects, particularly in the setting of an open ductus. Despite the increase in PVR, the shunt in VGAM is obligatory, such that pulmonary vasoconstriction does not offset the high-output cardiac failure, as might occur in congenital cardiac disease. This is postulated as a contributor to the severity of cardiac failure in infants with VGAM.

Acute pulmonary hypertension secondary to left ventricular dysfunction

Poor function of the left ventricle results in inefficient ejection of end-diastolic volume, which results in a progressive increase in left ventricular end-diastolic pressure (LVEDP). This leads to pulmonary venous congestion, increased pulmonary capillary pressure, and a hydrostatic gradient across the interstitium, resulting in fluid transudation to alveolar spaces, i.e., pulmonary edema. Similar to left-to-right shunt lesions, endothelial dysfunction is also implicated as contributory to elevated pulmonary pressure in obstructive pulmonary venous hypertension. Left and right ventricular dysfunction may coexist in transitional aPH, although there are subgroups in whom LV disease may occur independently. Fetal and neonatal echocardiographic studies of infants with congenital diaphragmatic hernia (CDH) support disturbances of fetal LV development and postnatal LV dysfunction as part of the pathogenesis of hypoxemia in affected infants. Early LV systolic function correlates with markers of clinical disease severity in CDH and may be a primary determinant of illness severity rather than a secondary consequence of cardiovascular instability. These findings have implications for treatment, and use of pulmonary vasodilators, since increasing pulmonary blood flow and LV preload may risk exacerbating existing LV diastolic dysfunction and pulmonary venous hypertension. ^, Flash pulmonary edema has been observed with pulmonary vasodilator therapy in pulmonary venous disease. Conversely, improvements in RV performance by afterload reduction may indirectly augment LV performance through ventricular interdependence. A multicenter randomized trial of sildenafil and inhaled NO in CDH (CoDiNOS trial) utilizing cardiac function assessment may provide additional guidance on use of pulmonary vasodilators in this setting. In general, pulmonary vasodilators should be used with caution in infants with LV dysfunction and are likely to be harmful where LV impairment is severe.

Chronic pulmonary hypertension secondary to BPD

Chronic PH associated with BPD (BPD-cPH) is characterized by abnormal remodeling and growth arrest of the pulmonary vasculature, ^, and impaired angiogenesis and alveolarization, ^, resulting in abnormal pulmonary vascular function with increased PVR, high RV afterload, and RV dysfunction. Abnormal pulmonary vascular remodeling is triggered by postnatal hypoxia/hyperoxia. Additive insults, such as endothelial dysfunction, and inflammatory stimuli, such as infection and ventilator-induced lung injury, are thought to perpetuate alveolar hypoxia ^{, ,} in at-risk infants. Antenatal factors, including inflammation, intrauterine growth restriction, and the lung microbiome, are also implicated in the pathogenesis. There is evidence that echocardiographic evidence of PH within the first 7–14 days after birth may predict subsequent moderate-severe BPD or death at 36 weeks postmenstrual age, ^, underscoring the importance of abnormal pulmonary vascular development in the development of BPD. Conversely, a very low risk of late PH has been observed in the absence of PH at 7 days of age. The approach to management includes lung optimization alongside treatment with pulmonary vasodilators (e.g., sildenafil). Both clinical improvement and reductions in pulmonary artery pressure have been documented with sildenafil therapy. In the presence of RV dilatation, diuretics may also be considered for optimizing RV configuration. Although long-term benefits of diuretics have not been demonstrated in infants with BPD, improvements in both oxygenation and pulmonary mechanics have been observed. In addition, a retrospective study demonstrated high rates of symptomatic improvement in BPD-cPH, with diuretic treatment where RV dilatation was used as the treatment threshold.